In silico exploration of anticancer plant phytochemicals for EGFR-targeted lung cancer therapy.

Mutations in the epidermal growth factor receptor (EGFR), particularly in the tyrosine kinase domain such as exon 19 deletions and the L858R point mutation, play a critical role in the development of non-small cell lung cancer (NSCLC). EGFR is a well-established therapeutic target in the management of NSCLC. In this study, we targeted the mutated EGFR kinase domain (L858R) using its crystal structure (PDB ID: 2EB3) to design EGFR tyrosine kinase inhibitors. We curated a library of 687 phytoconstituents from four anticancer plants (Camellia sinensis, Curcuma longa, Ginkgo biloba, and Vitis vinifera) using the IMPPAT database. Kaempferol, morin, and isorhamnetin, all from Ginkgo biloba, emerged as promising candidates. Drug-likeness and ADMET analyses were performed to evaluate the pharmacokinetic and safety profiles of these compounds. Pharmacophore modeling and bioactivity score analysis were also conducted. Finally, molecular dynamics (MD) simulations were performed to assess the stability of the EGFR-ligand complexes. The docking studies revealed high binding energies for kaempferol (- 8.5 kcal/mol), morin (- 8.5 kcal/mol), and isorhamnetin (- 8.7 kcal/mol) with the ATP-binding site of EGFR, compared to the reference drug, erlotinib (- 7 kcal/mol). These compounds exhibited superior pharmacokinetic properties, including high gastrointestinal absorption and non-inhibition of P-glycoprotein activity, unlike erlotinib. Toxicity predictions showed mild immunotoxicity for morin and isorhamnetin, with all compounds demonstrating no hepatotoxicity and no inhibition of CYP3A4 or CYP2D6 enzymes. Structural analysis highlighted the hydroxyl groups in the selected compounds as key for hydrogen bond (H-bond) formation with EGFR residues, enhancing their inhibitory potential. MD simulations confirmed the stability of EGFR complexes with the selected compounds, showing lower average RMSD values and better convergence compared to the EGFR-erlotinib complex. This research underscores the potential of kaempferol, morin, and isorhamnetin as novel EGFR inhibitors derived from Ginkgo biloba for NSCLC treatment. These compounds demonstrated strong binding affinities, favorable pharmacokinetic properties, and stability in silico. Further in vitro and in vivo validation is necessary to confirm their efficacy against mutated EGFR in NSCLC.